Thieno[3,2-c]pyridine derivatives of formula (1) are known to exhibit high blood platelet aggregation inhibitory and anti-thrombotic activities and can be beneficially used as a blood circulatory drug in the treatment of peripheral artery diseases such as cerebral apoplexy, thrombus, and embolism, or coronary artery diseases such as myocardial infarction and angina pectoris:
wherein R is hydrogen or methoxycarbonyl.
The compound of formula (1) wherein R is hydrogen is called ticlopidine, and the compound of formula (1) wherein R is methoxycarbonyl is called clopidogrel (see U.S. Pat. Nos. 4,051,141, 4,529,596 and 4,847,265).
Ticlopidine and clopidogrel have been hitherto synthesized by methods collectively shown in Reaction Scheme A (see U.S. Pat. Nos. 4,127,580, 4,174,448, 6,043,368, 4,529,596, 4,847,265 and 5,204,469, British Patent No. 2,166,730, European Patent Publication No. 0 522 956 A, and International Publication Nos. WO 98/51689 and WO 02/59128):

As shown in Reaction Scheme 1, ticlopidine of formula (1a) may be synthesized by reacting 2-(2-aminoethyl)thiophene of formula (a) with a compound of formula (b) (wherein L represents a leaving group such as chloro) or reacting a compound of formula (c) (wherein L represents a leaving group such as p-toluenesulfonyl) with a o-chlorobenzylamine derivative of formula (d), to obtain a compound of formula (e), and then cyclizing the compound (e) with a formylating agent such as formaldehyde, A-CH2-B (wherein A represents a halogen, alkoxy, alkylthio or amino group, and B represents an alkoxy, alkylthio, amino or alkoxycarbonyloxy group) or a heterocyclic compound of formula
wherein W represents O, NH or S.
Alternatively, ticlopidine of formula (1a) may also be synthesized by directly cyclizing 2-(2-aminoethyl)thiophene of formula (a) with a formylating agent to obtain 4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (f), and then reacting the compound (f) with a compound of formula (b).
Analogously, clopidogrel racemate of formula (1c) can be obtained according to the above method, but the racemate must be converted into the optically pure clopidogrel of formula (1b) through a complicated optical resolution process which comprises reacting the racemate of formula (1c) with an optically-active acid, e.g., (1R)-(−)-camphosulfonic acid, to obtain a diastereoisomeric salt of formula (g), subjecting the diastereomeric salt to a series of fractional crystallization processes to increase the optical purity, and then removing the residual optically-active acid from the product. Thus, this method produces the compound of formula (1b) at a low yield.
Accordingly, the present inventors have been studied to develop a simple method of preparing an optically pure clopidogrel, and found that when a specified thiophene derivative is reacted with an optically active 2-chlorobenzylamine derivative, the optically pure clopidogrel can be obtained at a high yield in a simple manner together with ticlopidine.